Hindawi Publishing Corporation Oxidative Medicine and Cellular Longevity Volume 2016, Article ID 8378613, 19 pages http://dx.doi.org/10.1155/2016/8378613 Review Article A Potential Alternative against Neurodegenerative Diseases: Phytodrugs Jesús Pérez-Hernández,1,2 Víctor Javier Zaldívar-Machorro,1,3 David Villanueva-Porras,1,4 Elisa Vega-Ávila,5 and Anahí Chavarría1 1 DepartamentodeMedicinaExperimental,FacultaddeMedicina,UniversidadNacionalAutonoma´ de Mexico,´ 06726 Mexico,´ DF, Mexico 2Posgrado en Biolog´ıa Experimental, Universidad Autonoma´ Metropolitana-Iztapalapa, 09340 Mexico,´ DF, Mexico 3Programa de Becas Posdoctorales, Universidad Nacional Autonoma´ de Mexico,´ 04510 Mexico,´ DF, Mexico 4Posgrado en Ciencias Biomedicas,´ Universidad Nacional Autonoma´ de Mexico,´ 04510 Mexico,´ DF, Mexico 5Division´ de Ciencias Biologicas´ y de la Salud, Universidad Autonoma´ Metropolitana, 09340 Mexico,´ DF, Mexico Correspondence should be addressed to Anah´ıChavarr´ıa; [email protected] Received 3 July 2015; Revised 2 November 2015; Accepted 5 November 2015 AcademicEditor:AnandhB.P.Velayutham Copyright © 2016 Jesus´ Perez-Hern´ andez´ et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Neurodegenerative diseases (ND) primarily affect the neurons in the human brain secondary to oxidative stress and neuroinflam- mation. ND are more common and have a disproportionate impact on countries with longer life expectancies and represent the fourth highest source of overall disease burden in the high-income countries. A large majority of the medicinal plant compounds, such as polyphenols, alkaloids, and terpenes, have therapeutic properties. Polyphenols are the most common active compounds in herbs and vegetables consumed by man. The biological bioactivity of polyphenols against neurodegeneration is mainly due to its antioxidant, anti-inflammatory, and antiamyloidogenic effects. Multiple scientific studies support the use of herbal medicine in the treatment of ND; however, relevant aspects are still pending to explore such as metabolic analysis, pharmacokinetics, and brain bioavailability. 1. Introduction the high-income countries. According to the World Health Organization, 37 million people currently have dementia Neurodegenerative diseases (ND) such as Alzheimer’s (AD) and Parkinson’s disease (PD) and multiple sclerosis (MS) worldwide, and about 50% of them are being affected by primarily affect the neurons in the human brain and are AD and this number is expected to grow up to 115.4 million characterized by deterioration of neurons or myelin sheath, people by 2050 [4]. sensory information transmission disruption, movement Recently, a great number of natural medicinal plants have control,andmore[1].ThegreatestriskfactorforNDisaging, been tested for their therapeutic properties, showing that which carries mitochondrial dysfunction, chronic immune- therawextractsorisolatedpurecompoundsfromthem inflammatory response, and oxidative stress [2, 3], the major have more effective properties than the whole plant as an causes of neuronal damage and death. Nowadays, ND are alternative for the treatment of ND. These properties are due chronic and incurable conditions whose disabling effects may mainly to the presence of polyphenols (Figure 1), alkaloids continue for years or even decades representing an enormous (Figure 2), and terpenes (Figure 3(d)), among others, that are disease load, regarding human suffering and economic cost. micronutrients produced by plants as secondary metabolites The ND are more common and have a disproportionate [5, 6]. There is substantial evidence (epidemiological studies, impact on countries with longer life expectancies and rep- animal studies, and human clinical trials) that indicates that resent the fourth highest source of overall disease burden in polyphenols reduce a wide range of pathologies associated 2 Oxidative Medicine and Cellular Longevity R2 OH OH OH O R1 R3 OH R1 R1 O O R4 OH HO OH HO OH HO O R2 HO HO O (a) (b) (c) (d) O OH HO HO HO O O O HO O R1 OH O OH (e) (f) (g) (h) OH O OH OH HO O R1 O O O R2 O O HO O O O OH R5 O HO OH O OH OH O HO R4 HO O O R3 O (i) (j) (k) OH R1 R1 R2 OH R2 R5 O HO O R5 O R1 R4 OH OH R4 R3 O OH R3 O (l) (m) (n) HO O R1 H − O X OH H H + OH O HO R2 HO O H O R4 R3 OH OH OH O (o) (p) Figure 1: Representative polyphenol compounds. (a) Benzoic acids: -hydroxybenzoic acid R1 =R3 =R4 =H,R2 = OH; protocatechuic acid R1 =R4 =H,R2 =R3 = OH; gallic acid R1 =R2 =R3 =OH,R4 = H; and salicylic acid R1 =R2 =R3 =H,R4 = OH. (b) Hydroxycinnamic acids: coumaric acid R1 =R2 = H; caffeic acid R1 =OH,R2 = H; ferulic acid R1 =OMe,R2 = H; and sinapic acid R1 =R2 =OMe.(c)Stilbenes: resveratrol R1 = H; oxyresveratrol R1 = OH. (d) Hydroxycinnamoyl ester: chlorogenic acid. (e) Hydroxycinnamoyl derivatives: gingerol; (f) Chavicol R1 = H; eugenol R1 = OMe; (g) curcumin; (h) magnolol; and (i) echinacoside. Flavonoid compounds. (j) Nobiletin; (k) Flavones: apigenin R1 =R4 =H,R2 =R3 =R5 =OH;baicaleinR1 =R2 =H,R3 =R4 =R5 =OH;chrysinR1 =R2 =R4 =H,R3 =R5 = OH; and luteolin R4 =H,R1 =OMe,R2 =R3 =R5 = OH. (l) Flavonols: kaempferol R1 =R4 =H,R2 =R3 =R5 = OH; quercetin R4 =H,R1 =R2 =R3 =R5 = OH. (m) Flavanols (+)-catechin R1 = H; (+)-gallocatechin R1 = OH. (n) Flavanones: hesperetin R4 =H,R1 =R3 =R5 =OH,R2 =OMe; naringenin R1 =R4 =H,R2 =R3 =R5 = OH; pinocembrin R1 =R2 =R4 =H,R3 =R5 = OH. (o) Anthocyanins: aurantinidin R1 =R2 =H, R3 =R4 = OH; cyanidin R2 =R4 =H,R1 =R3 = OH; pelargonidin R1 =R3 =R4 =H,R2 = OH; and peonidin R2 =R4 =H,R1 =OMe,R3 = OH. (p) Flavonolignans: silydianin. Oxidative Medicine and Cellular Longevity 3 HO HO O O O R1 O HN O + N N N H O O N O OH O O S S (a) (b) (c) (d) (e) O S S C N (f) Figure 2: Some alkaloid compounds in plants. (a) Capsaicin; (b) protoberberines: jatrorrhizine R1 =OH,palmatineR1 = OMe; (c) vincamine; (d) piperine; (e) diallyl sulfide; and (f) sulphoraphane. H O O 6 10 – H NH2 HO O O H HO N O HO O O O HO OH (a) (b) (c) (d) Figure 3: Some miscellaneous antioxidant compounds from plants. (a) Coenzyme Q6–10; (b) l-theanine; (c) ascorbic acid; and (d) lycopene. with inflammation [7–9]. The main mechanisms of polyphe- 2. Etiology of Neurodegenerative Diseases nols include their well-characterized antioxidant effects [10, ND are incurable and disabling conditions secondary to 11], inhibition of intracellular kinases activity [12], binding progressive neuronal loss, which leads to chronic brain to cell surface receptors [13], and modifying cell membrane damage and neurodegeneration. The etiology of ND is still functions [14]. Also, recently the neuroprotective effects unknown, although several ND animal models showed asso- of polyphenols have been described in several models of ciated damage with the blood-brain barrier, protein aggrega- ND and involve mainly signaling pathways mediators [15], tion, toxin exposure, and mitochondrial dysfunction, which modulation of enzymes in neurotransmission [16, 17], inhi- lead to oxidative stress and inflammation, and consequently bition of neurotoxicity via ionotropic glutamate receptors neuronal death [21]. [18], antiamyloidogenic [19], and anti-inflammatory effects The blood-brain barrier controls the internal environ- [20]. This review focuses on the plant extracts or compounds ment of the vertebrate CNS and represents the border isolated from plants that may hold potential in the treatment between the capillary and the extracellular fluid of CNS neu- of the principal ND. rons and glial cells; it also ensures specific brain homeostasis 4 Oxidative Medicine and Cellular Longevity allowing adequate neuronal function [22]. Neurovascular The proteins aggregation also plays an important role changes normally occur as part of aging, but these are more in mitochondrial dysfunction; for example, the accumu- evident in chronic ND [23]. About 20% of blood flow lation of mitochondrial A aggregates has been observed decreases in the aged brain, which associates with reduced both in patients and in transgenic models of AD [42–44]. protein synthesis [24]. Interestingly, this blood flow reduction Additionally, inhibition of mitochondrial complex I occurs is higher in the presence of any ND, which may lead to in PD patients [45] and the two principal models used changes in intracellular pH and accumulation of interstitial for the study of PD. Rotenone—a natural compound used lactateandglutamate[23,25].Thesechangesareobservedin as an insecticide, piscicide, and pesticide—and 1-methyl- specific brain regions in diseases such as AD, PD, MS among 4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)—a neurotoxin + other CNS disorders [25–28]. precursor of 1-methyl-4-phenylpyridinium (MPP ), which Abnormal protein aggregation of specific regions and destroys dopaminergic neurons in the substantia nigra— neuronal populations is a common feature among ND. For both act by inhibiting mitochondrial complex I [21]. In ALS, example, the -synuclein inclusions in dopaminergic neu- mitochondrial SOD1 enzyme aggregates cause loss of mito- rons from the substantia nigra are the main histopathological chondrial function and induce cellular death by apoptosis marker in PD [29]. Also, insoluble aggregates of the amyloid [46]. This phenomenon is present in almost all ND and beta-peptide (A) and neurofibrils composed of Tau protein associated with inflammation, which is one of the points of are found in AD [30, 31] and hyperphosphorylated Tau aggre- therapeutic interest and study. gation in demyelination areas in MS [32]. Finally, superoxide The CNS inflammation is dependent on inflamma- dismutase 1 (SOD1) aggregations are present in amyotrophic tory mediators produced mainly by glial cells, specifically lateral sclerosis (ALS) [33]. The main relevance of protein microglia and CNS macrophages [47]. Microglial activation aggregates is that they lead to mitochondrial dysfunction is crucial in the pathogenesis and the course of PD [48], AD inducing apoptotic neuronal death.